Implantable sensor and method for detecting at least one analyte in a body fluid

ABSTRACT

Disclosed is a fully implantable sensor for detecting at least one analyte in a sample of body fluid. The sensor has a measurement chamber plate that receives the sample of bodily fluid and a quantum cascade laser illumination source that generates an illumination light beam in the spectral range and transmits it to the measurement chamber plate. The illumination light beam at least partially illuminates the measurement chamber plate and the measurement chamber plate generates a reflection light beam in response to the illumination by the illumination light beam. The reflection light beam at least partially illuminates the sample of body fluid within the measurement chamber plate. An optical detector detects at least one property of the reflection light beam and generates a sensor signal dependent on the presence of the analyte. A controlled evaluates the sensor signal. A method using an inventive fully implantable sensor is also disclosed.

RELATED APPLICATIONS

This application is a continuation of PCT/EP2018/051405, filed Jan. 22,2018, which claims priority to EP 17 152 684.1, filed Jan. 23, 2017, theentire disclosures of each of which are hereby incorporated herein byreference.

BACKGROUND

This disclosure relates to an implantable sensor element and a kit fordetecting at least one analyte in a body fluid as well as to a methodfor detecting at least one analyte. The devices and methods according tothis disclosure may mainly be used for long-term monitoring of ananalyte concentration in a body fluid, such as for long-term monitoringof a glucose level or of the concentration of one or more other types ofanalytes in a body fluid. This disclosure may both be applied in thefield of home care and in the field of professional care, such as inhospitals. Other applications are feasible.

Monitoring certain body functions, more particularly monitoring one ormore concentrations of at least one metabolite concentration in a bodyfluid plays an important role in the prevention and treatment of variousdiseases. Such metabolites can include by way of example, but notexclusively, blood glucose, lactate, cholesterol or other types ofanalytes and metabolites. Without restricting further possibleapplications, this disclosure will be described in the following textwith reference to blood-glucose monitoring. However, additionally oralternatively, this disclosure can also be applied to other types ofanalytes.

Conventional devices for determining analyte concentrations are in manycases based on generating a sample of a body fluid, for example a dropof blood, which is then tested with respect to its analyte content.Continuous surveillance of the body's glucose concentration cansignificantly improve the treatment and precaution of long-termcomplications of diabetes patients. Typically devices for continuousglucose monitoring are meant for minimally-invasive short-term use, forexample shorter than 14 days, and are based on an electrochemicaldetection scheme, in particular on the enzymatic digestion of glucose.Transcutaneous sensor systems typically imply a large number oftechnical challenges. Thus, a first challenge resides in the fact thatthe lifetime of a sensor is limited. A sensor is generally worn forapproximately one week. After that, influences such as enzymes beingused up and/or a sealing off in the body generally reduce thesensitivity of the sensor, or it is expected that the sensor fails.However, long-term continuous glucose monitoring, for example for termsof around one year, is desirable for several applications. Sensors forlong-term monitoring based on optical systems are an area of currentresearch.

Optical systems generally use at least one sensor material which changesat least one optically measurable property in the presence of one ormore specific analytes. Alternatively absorption methods may be used.For example, U.S. Publication No. 2007/0004974 describes an apparatusfor assaying an analyte in a body comprising: at least one light sourceimplanted in the body controllable to illuminate a tissue region in thebody with light at at least one wavelength that is absorbed by theanalyte and as a result generates photoacoustic waves in the tissueregion; at least one acoustic sensing transducer coupled to the bodythat receives acoustic energy from the photoacoustic waves and generatessignals responsive thereto; and a processor that receives the signalsand processes them to determine a concentration of the analyte in theilluminated tissue region.

In principle, sensors based on mid-infrared technology may be used forlong-term continuous glucose monitoring. Mid-infrared radiation can beused for excitation of fundamental oscillation modes of biomolecules,such as for quantitative determination of glucose. Beside spectroscopicdetection of glucose using photoacoustic and photothermic methods,quantitative determination of glucose may be performed via absorptionspectroscopy. However, for in vivo measurements using mid-infraredradiation absorption spectroscopy skin heterogeneity and, becausetypically relative change of absorption spectrum due to glucoseconcentration is small, high absorption coefficient of water are majorchallenges.

Quantum cascade lasers (QCLs) are known as mid-IR radiation source withuniquely high spectral power density. Because of high spectral powerdensity of QCLs the high absorption coefficient of water can be overcomeby using QCLs and, thus, allowing quantitative determination of glucose.For example, C. Vrančić et al., “Continuous glucose monitoring by meansof mid-infrared transmission laser spectroscopy in vitro”, Analyst,2011, 136, 1192-1198 and C. Vrančić et al., “A Quantitative Look Insidethe Body: Minimally Invasive Infrared Analysis in Vivo”, Anal. Chem.,2014, 86 1836-1845 describe implantable fiber-based sensors usingmid-infrared laser spectroscopy. Such fiber-based sensors comprise afiber transmitting light in the mid-infrared spectral range and having acentral cavity as measurement volume. Molecules of interstitial fluidare transported via diffusion into the measurement volume and can bedetermined quantitatively via an absorption measurement.

U.S. Pat. No. 8,040,526 B2 describes an implantable product whichincludes an optical cavity structure with first and second parts, eachof which can operate as an optical cavity. The first part includes acontainer with at least one opening through which bodily fluid cantransfer between the container's interior and exterior when the productis implanted in a body. The second part includes a container that isclosed and contains a reference fluid. The implantable product can alsoinclude one or both of a light source component and a photosensingcomponent. Photosensed quantities from the first part's output light canbe adjusted based on photosensed quantities from the second part'soutput light. Both parts can have their light interface surfaces alignedso that they both receive input light from a light source component andboth provide output light to a photosensing component.

U.S. Publication No. 2012/059232 A1 describes an apparatus including asupport configured to be implanted within a body of a subject and asampling region coupled to the support. The apparatus is configured topassively allow passage through the sampling region of at least aportion of fluid from the subject. The apparatus also includes anoptical measuring device in optical communication with the samplingregion. The optical measuring device comprises at least one light sourceconfigured to transmit light through at least a portion of the fluid,and at least one sensor configured to measure a parameter of the fluidby detecting light passing through the fluid.

U.S. Publication No. 2008/231857 A1 describes a sensor system fordetection of a gaseous chemical substance, which includes an opticalsampling cell holding a sampling chamber of a volume of at most 20 mm3,a light emitter and a light receiver. The sampling cell is adapted forfree-space, single monomodal propagation of the light beam.

U.S. Publication No. 2010/121163 A1 describes optical microneedles whichare adapted for near-infrared or mid-infrared in vivo spectroscopicsensing; and provide a MEMS-based spectrometer for continuous lactateand glucose monitoring by means of a near-infrared or mid-infraredoptical microneedle array in a transdermal patch.

However, despite the advantages of such known fiber-based sensors,fiber-based sensors have considerable disadvantages in practice. Opticalfibers in practice have considerable sensitivity to mechanicalinfluences, for example due to mechanical loads during implantationand/or removal and during wearing and monitoring in the body.Furthermore, sensor design of known fiber-based sensors leads to atleast two permanent injuries of the skin for implantation which maylimit wearing comfort and may permit ingress of contaminations. Inaddition, known fiber-based sensors require filtration of interstitialfluid for quantitative determination of glucose via infrared absorptionspectroscopy in order to ensure functionality of the sensor. Themeasurement volume has to be membrane shielded and protected frommacromolecules, for example by using a semipermeable membrane. However,implementation of such a membrane into the sensor design of knownfiber-based sensors is difficult without increasing diffusion course andthus worsening response behavior of the sensor. Further, availability ofsuch membranes is limited. Furthermore, known infrared fibers such aschalcogenide fibers, coated hollow fibers and silver halide fibers arecytotoxic and require a, e.g., polyethylene coating in order to be usedin the body.

SUMMARY

This disclosure provides an implantable sensor element and methods fordetermining at least one analyte in a sample of body fluid, which avoidthe above-described disadvantages of known sensors and methods. Inparticular, the implantable sensor element should permit reliablereagent-free continuous monitoring of glucose in a sample of body fluidand mechanical stability such as enhanced wearing comfort and reducedingress of contaminations.

As used in the following, the terms “have,” “comprise” or “include” orany arbitrary grammatical variations thereof are used in a non-exclusiveway. Thus, these terms may both refer to a situation in which, besidesthe feature introduced by these terms, no further features are presentin the entity described in this context and to a situation in which oneor more further features are present. As an example, the expressions “Ahas B,” “A comprises B” and “A includes B” may both refer to a situationin which, besides B, no other element is present in A (i.e., a situationin which A solely and exclusively consists of B) and to a situation inwhich, besides B, one or more further elements are present in entity A,such as element C, elements C and D or even further elements.

Further, as used in the following, the terms “preferably,” “morepreferably,” “particularly,” “more particularly,” “specifically,” “morespecifically” or similar terms are used in conjunction with optionalfeatures, without restricting alternative possibilities. Thus, featuresintroduced by these terms are optional features and are not intended torestrict the scope of the claims in any way. The invention may, as theskilled person will recognize, be performed by using alternativefeatures. Similarly, features introduced by “in an embodiment of theinvention” or similar expressions are intended to be optional features,without any restriction regarding alternative embodiments of theinvention, without any restrictions regarding the scope of the inventionand without any restriction regarding the possibility of combining thefeatures introduced in such way with other optional or non-optionalfeatures of the invention.

It shall be understood for purposes of this disclosure and appendedclaims that, regardless of whether the phrases “one or more” or “atleast one” precede an element or feature appearing in this disclosure orclaims, such element or feature shall not receive a singularinterpretation unless it is made explicit herein. By way of non-limitingexample, the terms “measurement chamber plate,” “illumination source”and “reflection light beam,” to name just a few, should be interpretedwherever they appear in this disclosure and claims to mean “at leastone” or “one or more” regardless of whether they are introduced with theexpressions “at least one” or “one or more.” All other terms used hereinshould be similarly interpreted unless it is made explicit that asingular interpretation is intended.

In a first aspect of this disclosure, an implantable sensor element fordetecting at least one analyte in a sample of body fluid is disclosed.

The sensor element comprises at least one measurement chamber plateadapted to receive the sample of bodily fluid. The sensor elementcomprises at least one illumination source designed to generate at leastone illumination light beam in at least one spectral range and totransmit the illumination light beam to the measurement chamber platesuch that the illumination light beam at least partially illuminates themeasurement chamber plate. The measurement chamber plate is designed togenerate at least one reflection light beam in response to theillumination by the illumination light beam such that the reflectionlight beam at least partially illuminates the sample of body fluidwithin the measurement chamber plate. Preferably, the sample of bodyfluid may be illuminated at least twice within the measurement chamberplate. The sample may be illuminated, firstly, by the illumination lightbeam, for example in a first direction, and, subsequently, by thereflection light beam, for example, in a second direction.

The sensor element comprises at least one optical detector designed todetect at least one property of the reflection light beam and togenerate at least one sensor signal dependent on the presence of theanalyte. The sensor element furthermore comprises at least one controlunit (also referred to as a “controller”) designed to evaluate thesensor signal.

As used herein, the term “implantable” refers to the fact that thesensor element is adapted to have appropriate dimensions to be insertedinto the body tissue of the user, such as into subcutaneous tissue, and,further, that the sensor element is biocompatible in order to remain inthe body tissue for an elongated time period, such as for several daysor even several weeks or several months. Thus, as an example, the sensorelement may have a biocompatible coating and/or may be biocompatible.The term “implant” refers to the fact that the sensor element may beinserted fully or partially into the body tissue. Thus, in thefollowing, the terms “implant” and “insert” will be used as synonyms.The sensor element is a fully implantable sensor element. The term“fully implantable” further refers to that the sensor element may bedesigned such that all parts of the sensor element can be fullyimplanted into the body tissue, in particular without any part of thesensor element protruding through the skin of the user, i.e., a fullsubcutaneous implantation. Generally, during implantation and/or duringuse of the sensor element, the sensor element may fully or partiallypenetrate the skin of the user. Thus, the sensor element preferably maybe embodied as a fully implantable transcutaneous sensor element.

As used herein, the term “sensor element” generally refers to a unit,which may be handled as one entity, comprising the at least onemeasurement chamber plate, at least one illumination source, at leastone optical detector and at least one control unit. The sensor elementmay be adapted to perform at least one absorption measurement.

As used herein, the term “detecting” refers to a quantitative and/orqualitative determination of an analyte concentration, i.e., adetermination of the amount and/or concentration of the analyte in thebody fluid and/or the response to the question of whether the analyte ispresent in the body fluid. As further used herein, the term “analyte”may refer to an arbitrary element, component or compound which may bepresent in a body fluid and the concentration of which may be ofinterest for a user. Preferably, the analyte may be or may comprise anarbitrary chemical substance or chemical compound which may take part inthe metabolism of the user, such as at least one metabolite. As anexample, the at least one analyte may be selected from the groupconsisting of glucose, cholesterol, triglycerides, lactate. Additionallyor alternatively, however, other types of analytes may be used and/orany combination of analytes may be determined. As generally used withinthis disclosure, the term “user” may refer to a human being or ananimal, independent from the fact that the human being or animal,respectively, may be in a healthy condition or may suffer from one ormore diseases. As an example, the user may be a human being or an animalsuffering from diabetes. However, additionally or alternatively, thisdisclosure may be applied to other types of users.

Generally, an arbitrary type of body fluid may be used. (The terms “bodyfluid” and “bodily fluid” are used synonymously herein.) Preferably, thebody fluid is a body fluid which is present in a body tissue of theuser, such as in the interstitial tissue. Thus, as an example, the bodyfluid may be selected from the group consisting of blood andinterstitial fluid. However, additionally or alternatively, one or moreother types of body fluids may be used. The body fluid generally may becontained in a body tissue. Thus, generally, the detection of the atleast one analyte in the body fluid may preferably be determined invivo.

The sensor element comprises at least one measurement chamber plateadapted to receive the sample of bodily fluid. As used herein, the term“measurement chamber plate” refers to an element adapted to receive thesample of body fluid having a sheet or plate-like geometry. Themeasurement chamber plate may have a flat geometry. The measurementchamber plate may comprise a monolithic or a multi-plate setup. Thesheet or plate-like structure geometry may enhance mechanical stabilityund thus robustness of a measurement signal. As further used herein, theterm “receive” the sample of body fluid refers to the fact that themeasurement chamber plate is adapted to one or more of permittingingress of body fluid, contacting with body fluid and being in exchangewith the body fluid. The measurement chamber plate may be designed suchthat the analyte concentration within the measurement chamber isadjusted and/or adapted, for example by diffusion processes, to theanalyte concentration of the ambient body fluid. The measurement chamberplate may receive the sample of body fluid via diffusion processes.Filling the sample via diffusion processes may ensure maintenance-freeoperation of the implanted sensor element. The measurement chamber platemay comprise at least one hydrogel as diffusion permeable material.

The measurement chamber plate is designed to generate at least onereflection light beam in response to the illumination by theillumination light beam such that the reflection light beam at leastpartially illuminates the sample of body fluid within the measurementchamber plate. Preferably, the sample of body fluid is illuminated bythe illumination light beam before the sample of body fluid isilluminated by the reflection light beam. The reflection light beam maybe adapted to illuminate the sample of body fluid. The reflection lightbeam may illuminate a volume of the sample of body fluid. As usedherein, the term “reflection light beam” refers to at least one lightbeam reflected by the measurement chamber plate. The measurement chamberplate may comprise at least one reflector element and/or may comprise areflective material such as a reflective coating. The measurementchamber plate may be adapted to at least partially reflect theillumination light beam. The term “at least partially reflect” refers toa complete or partial reflection of the illumination light beam. Forexample, the measurement chamber plate, in particular at least onereflector of the measurement chamber, may be adapted to reflect morethan 20% of the illumination light beam, preferably more than 50% of theillumination light beam, most preferably more than 80% of theillumination light beam. As further used herein, the term “at leastpartially illuminates the sample of body fluid” refers to the fact thatthe reflection light beam may completely or partially illuminate thesample of body fluid. For example, the reflection light beam mayilluminate more than 5% of the sample of body fluid, preferably morethan 10%, more preferably more than 25% of the sample of body fluid.However, other embodiments are feasible. The measurement chamber platemay be designed such that the reflection light beam illuminates a volumeof the sample as large as possible.

The measurement chamber plate may comprise at least one membraneelement. The membrane element may be adapted to protect the measurementchamber plate from penetration of particles above a certain size such aslarge sized molecules like proteins and/or cells like leukocytes.

The measurement chamber plate may comprise at least one chamber wall,wherein the chamber wall is adapted to receive the sample of body fluid.The sensor element may be adapted to perform at least one measurementbased on absorption spectroscopic techniques using a miniaturized fluidcell. The measurement chamber plate may be adapted to receive a samplesize of body fluid such that a reliable absorption measurement can beperformed. For example, a layer thickness of body fluid in themeasurement chamber plate may be between 1 μm and 100 μm, preferablybetween 5 μm and 50 μm, more preferably the layer thickness may bebetween 8 μm and 15 μm. For example, the layer thickness may be 10 μm inorder to ensure high sensitivity to detect glucose in aqueous solution.The chamber wall may be adapted to have a first side at least partiallypermeable to light, for example in the infrared spectral range, and asecond side at least partially permeable to the sample of body fluid. Asused herein, “permeable to light” refers to at least partially permit alight beam, for example the illumination light beam and/or thereflection light beam, to pass through. Thus, the first side of thechamber wall may be at least partially transparent. As used herein,“permeable to the sample of body fluid” refers to at least partialpermit ingress into and/or permit pass through the sample of body fluidinto the measurement chamber wall. The chamber wall may be arranged suchthat the side permeable to the sample of body fluid faces an exterior ofthe sensor element.

For example, the measurement chamber plate may comprise at least onefirst chamber wall adapted to be at least partially transparent to theillumination light beam. The first chamber wall may be designed as atleast one at least partially transparent first infrared window. Thefirst chamber wall may be arranged facing an interior of the sensorelement such as an interior surrounded by a housing of the sensorelement. The first chamber wall may face the illumination light beam.The first infrared window may be designed to let at least partially theillumination light beam through the infrared window to the sample ofbody fluid. For example, the infrared window may be designed to let atleast partially the illumination light beam pass through the infraredwindow into the measurement chamber plate. The first chamber wall may bedesigned as transmission window. The first chamber wall may be alight-permeable inner plate. The first chamber wall may bebiocompatible. The first chamber wall may comprise and/or may beproduced from at least one biocompatible material. The first chamberwall may consist fully of biocompatible material, for example abiocompatible material comprising at least one synthetic diamond orsilicon. The first chamber wall may comprise at least oneanti-reflective coating adapted to minimize reflections from a surfaceof the first chamber wall to the optical detector and/or reflections ofthe reflected beam back into the measurement chamber plate for examplein order to minimize interference effects on the signal. The firstchamber wall may comprise at least one micro-structured surface, e.g.,roughened surface adapted to minimize reflections from a surface of thefirst chamber wall to the optical detector and/or reflections of thereflected beam back into the measurement chamber plate for example inorder to minimize interference effects on the signal.

The measurement chamber plate may comprise at least one second chamberwall adapted to at least partially receive the sample of body fluid. Thesecond chamber wall may be a fluid-permeable outer plate. Themeasurement chamber plate may comprise at least one capillary elementarranged between the first chamber wall and the second chamber wall. Thecapillary element may be adapted to receive the sample of body fluid. Asused herein, the term “capillary element” generally refers to an elementwhich forms at least a part of a cuvette, cell or cavity for receivingand/or storage of the sample of body fluid. The receiving of the sampleof body fluid may be supported by capillary forces. The first and thesecond chamber walls may be arranged at opposing sides of a capillaryelement and form a measurement cuvette. The capillary element may bedesigned to receive an amount of body fluid required for reliabledetermination of the analyte. In order to obtain a maximum sensitivityof glucose in aqueous solution the capillary element may be designed toreceive a fluid layer thickness between 1 to 100 μm, preferably between5 μm and 50 μm, more preferably between 8 μm and 15 μm. For example, thecapillary element may be designed to receive a fluid layer thickness of10 μm. The capillary element may receive the sample of body fluid viadiffusion processes. In order to ensure suitable sensor responsebehavior, the capillary element may be designed such that diffusiondistances are as short as possible, preferably around 100 μm.

The measurement chamber plate may comprise at least one spacer elementarranged between the first chamber wall and the second chamber wall. Asused herein, the term “spacer element” refers to an arbitrary shapedelement adapted to adjust a distance between the first and secondchamber walls. The spacer element may have an arbitrary shape, forexample the spacer element may be at least one ring. The spacer elementmay have a thickness between 1 and 100 μm. The spacer element may be acut polyester film. Additionally or alternatively, one of the first andthe second chamber walls may comprise at least one cavity and/or recess,for example produced by photolithographic methods, adapted to form acapillary element.

The second chamber wall may be designed to be rigid against mechanicalinfluence, for example, during assembling of the sensor element, suchthat a constant measurement volume can be ensured. The second chamberwall may be designed to be permeable to the analyte, for example, toglucose, such that the analyte can reach the measurement chamber plate.The second chamber wall may be designed to prevent large-sized moleculesand/or cells to penetrate into the measurement chamber plate.

The second chamber wall may be designed as at least one at leastpartially reflective second infrared window. The second infrared windowmay comprise at least one reflective layer, for example a gold layer.The reflective layer may be arranged on at least one side of the secondinfrared window facing the illumination light beam in order to enhancereflection of the illumination light beam. The second infrared windowmay be designed to permit transport, for example by diffusion, of theanalyte into the capillary element. The second infrared window may be afluid-permeable outer plate. The second infrared window may comprise aplurality of holes. The second infrared window may comprise a pluralityof micro fluid channels. For example, the holes may be drilled microholes having diameter less than 100 μm, preferably less than 20 μm, morepreferably less than 10 μm. An average distance between two holes may beless than 500 μm, preferably less than 200 μm, more preferably less than100 μm. A thickness of the second infrared window may be less than 1000μm, preferably less than 500 μm. Such dimensions may ensure shortdiffusion times of glucose from interstitial fluid into the capillaryelement. The holes may have other shapes as for example slits orbendings. The holes may be produced using laser processing techniques orother methods known in the art, for example wet etching. The secondinfrared window may be or may comprise a silicon plate having aplurality of holes. Such a design can ensure proper rigidity. Thesilicon plate may be sputtered with a gold layer in order to enhancereflectivity. The second chamber wall may have a hydrophilic surfacestructure on one side and/or on the other side and/or in the holes ofthe wall adapted to have better fluidic properties. This hydrophilicsurface may be made by a microfabricated surface for example byphotolithographic or wet etching methods.

The measurement chamber plate may comprise further membrane elementssuch as flat membrane elements. The flat plate design of the measurementchamber plate may allow simple mounting of the flat membrane element. Incase of using the flat membrane element, the diffusion distance may beenhanced only slightly by the thickness of the flat membrane. Thefurther membrane element may be arranged on the side of the secondinfrared window and/or of the membrane element receiving the sample ofbody fluid. The further membrane element may be an ultra filtrationmembrane. The further membrane element may be adapted to reduceinfluence from proteins on the absorption measurement. Additionally oralternatively to a further membrane element, the holes of the secondinfrared window may be designed such that the second infrared windowfunctions as membrane such that no additional membrane element isrequired.

The second chamber wall may comprise the at least one membrane element.The second chamber wall may be designed as membrane element.Additionally or instead of the second infrared window, the secondchamber wall may be or may comprise the at least one membrane element.The membrane element may have reflective properties. For example, themembrane element may comprise at least one sintered metal. The membraneelement may be sputtered with a reflective layer such as a gold, silveror aluminum layer to enhance reflectivity. For example, the membraneelement may be selected from the group consisting of a track-etchedmembrane comprising polycarbonate; an Anodisc membrane comprisingaluminum oxide; a membrane having a supporting structure such as apolymeric microporous membrane available from Precision Membranes, LLC;a high-aspect-ratio membrane comprising silicon and/or carbon availablefrom Precision Membranes, LLC; a porous membrane comprising sinteredmetal. In one embodiment, the membrane element may be a membrane havinga supporting structure such as a polymeric microporous membraneavailable from Precision Membranes, LLC. The supporting structure may beadapted to provide rigidity to the measurement chamber plate. Themembrane element having a supporting structure may have a thickness ofseveral 10 μm such that the membrane element can be used as spacerelement. In a further embodiment, the membrane element may be ahigh-aspect-ratio membrane comprising silicon and/or carbon availablefrom Precision Membranes, LLC. The high-aspect-ratio membrane may have areflective coating, for example the membrane element may be sputteredwith a gold layer. The membrane element may have a reflective coating,for example, the membrane element may be sputtered with a gold layer.However, embodiments are feasible, without a reflective coating, e.g., aporous membrane comprising sintered metal has reflective properties inthe infrared spectral range.

The measurement chamber plate may comprise at least one attenuated totalreflection element. The attenuated total reflection element may compriseat least one ATR-crystal, for example an ATR-crystal available from ATRElements. The ATR-crystal may comprise a structured surface. TheATR-crystal may comprise at least one microstructure adapted to receivethe sample of body fluid. The microstructure may enhance amplificationof the sensor signal compared to ATR-crystals without microstructures.The microstructure may be adapted as capillary, wherein the receiving ofthe sample of body fluid may be supported by capillary forces. Themicrostructure may have hydrophilic properties such that themicrostructure is adapted to draw out the body fluid when in contactwith the interstitial fluid. Thereby a transition layer may be formedhaving a fixed thickness in which the reflection measurement can beperformed. The ATR-crystal may be arranged such that the illuminationlight beam is at least reflected once. Preferably, the illuminationlight beam may be reflected several times within the ATR-crystal. Theillumination light beam may be collimated by the at least one transferdevice, and may impinge on the ATR-crystal. The ATR-crystal may bedesigned such that the illumination light beam is reflected by an areaof the ATR-crystal comprising the body fluid. The ATR-crystal may bebiocompatible. The ATR-crystal may comprise or may be produced frombiocompatible material, for example silicon or diamond. The ATR-crystalmay be adapted to reflect the light beam such that it illuminates theoptical detector, for example after being collimated by at least onefurther transfer device. At least one ultra filtration membrane elementmay be arranged on the ATR-crystal.

The sensor element comprises at least one illumination source designedto generate at least one illumination light beam in at least onespectral range and to transmit the illumination light beam to themeasurement chamber plate such that the illumination light beam at leastpartially illuminates the measurement chamber plate. As used herein, theterm “light” generally refers to electromagnetic radiation in one ormore of the visible spectral range, the ultraviolet spectral range andthe infrared spectral range. The term visible spectral range generallyrefers to a spectral range of 380 nm to 780 nm. The term infrared (IR)spectral range generally refers to electromagnetic radiation in therange of 780 nm to 1000 μm, wherein the range of 780 nm to 2.5 μm isusually denominated as the near-infrared (NIR) spectral range, and therange from 25 μm to 1000 μm as the far-infrared (FIR) spectral range.The term mid-infrared (MIR) spectral range refers to the range from 2.5to 25 μm. Preferably, light as used within this disclosure is light inthe mid-infrared spectral range. As used herein, the term “light beam”generally refers to an amount of light emitted into a specificdirection. Thus, the light beam may be a bundle of the light rays havinga predetermined extension in a direction perpendicular to a direction ofpropagation of the light beam.

As further used herein, the term “illumination source” refers to atleast one device adapted to generate at least one light beam. As usedherein, the term “illumination light beam” refers to a light beamgenerated by the illumination source.

The illumination source may comprise at least one light source. Theillumination source may be a mid-IR radiation source. The illuminationsource may have a high spectral power density. The illumination sourcemay be adapted for quantitative determination of glucose in an aqueoussolution. The illumination source comprises at least one quantum cascadelaser. For example, the illumination source may comprise at least onequantum cascade laser chip. The quantum cascade laser may be aminiaturized quantum cascade laser. The quantum cascade laser may beselected from the group consisting of: at least one fixed-frequencyFabry-Pérot quantum cascade laser; at least one tunable external cavityquantum cascade laser; at least one distributed feedback quantum cascadelaser. For example, the illumination source may comprise at least onearray of quantum cascade lasers. The illumination source may be designedto be operated in pulsed or continuous mode. The sensor element maycomprise at least one pulser device adapted to operate the illuminationin the pulsed mode. The control unit may be adapted to control thepulser device. The sensor element may comprise at least one rechargeableenergy storage device, for example at least one lithium-ion battery,adapted to supply energy to the quantum cascade laser. The quantumcascade laser may have a low power consumption such that power supply bylithium-ion battery is possible.

The illumination light beam may have a wavelength in the infraredspectral range, preferably in mid-infrared spectral range. Theillumination source may be adapted to generate broadband illuminationlight or illumination light having a narrow bandwidth. The illuminationsource may be adapted to change the wavelength continuously over time.The illumination source may be adapted to generate a plurality ofillumination light beams, wherein each of the illumination light beamshas a different wavelength. The control unit may be adapted to one ormore of assign, adjust or select the wavelength of the illuminationlight beams. For example, the illumination source may comprise at leastone tunable distributed feedback quantum cascade laser and/or at leastone tunable external cavity quantum cascade laser having a narrowbandwidth. The control unit may be adapted to change the wavelengthcontinuously or non-continuously, for example within the mid-infraredspectral range. The control unit may be adapted to adjust and/or selectwavelengths suitable for identification of glucose and/or distinction ofglucose from further substances in the sample of body fluid, for examplesubstances present even after filtration such as maltose. Additionallyor alternatively, a broadband spectral range is used. For example, theillumination source may comprise at least one Fabry-Pérot quantumcascade laser. In order to permit absorption measurements with abroadband illumination source, the sensor element may comprise severaloptical detectors and suitable spectral bandpass filters or at least onetunable optical detector having at least one tunable, spectral bandpassfilter. The control unit may be adapted to rapidly switch betweenseveral different illumination light beams and/or several detectors toprobe different spectral regions.

As used herein, the term “at least partially illuminates the measurementchamber plate” refers to the fact that the illumination light beam maycompletely or partially illuminate the measurement chamber plate. Theillumination light beam may, preferably, at least partially illuminatethe sample of body fluid within the measurement chamber plate. Forexample, the illumination light beam may illuminate more than 5% of themeasurement chamber plate, preferably more than 10% of the measurementchamber plate, more preferably more than 25% of the measurement chamberplate. However, embodiments are feasible. The illumination light beammay illuminate the measurement chamber plate under an illumination anglebetween 0° and 85°, preferably between 20° and 60°, more preferablybetween 30° and 50°. For example, the illumination angle may be 45°. Theterm “illumination angle” refers to an angle between an axis ofincidence, i.e., a line perpendicular to a surface on which theillumination light beam impinges, and the illumination light beam.

The sensor element may comprise at least one modulation device formodulating the illumination light beam. The term “modulating of theillumination” should be understood to mean a process in which a totalpower of the illumination is varied, for example, with one or aplurality of modulation frequencies. For example, the modulation devicemay be designed for a periodic modulation, for example a periodic beaminterrupting device. The modulation can be effected for example in abeam path between the illumination source and the measurement chamberplate. For example the at least one modulation device may be arranged insaid beam path. The modulation device may be based on an electro-opticaleffect. The at least one modulation device may comprise, for example, amechanical shutter and/or a beam chopper or some other type of beaminterrupting device. Alternatively or additionally, however, it is alsopossible to use one or a plurality of different types of modulationdevices. The modulation device may comprise at least one filter element,for example at least one polarizer. In one embodiment, the illuminationsource itself can also be designed to generate a modulated illumination.For example, the illumination source may be embodied as a pulsedillumination source, for example as a pulsed laser. Thus, by way ofexample, the at least one modulation device can also be wholly or partlyintegrated into the illumination source.

The sensor element may comprise at least one transfer device. Thetransfer device may be adapted to collimate the illumination light beamand/or the reflection light beam. The transfer device may comprise atleast one optical lens, such as one or more convex lenses, one or morerefractive lenses, one or more collimating lenses. For example, thetransfer device may be arranged such that the illumination light beamtravels first through the at least one transfer device and thereafter tothe measurement chamber plate. The sensor element may comprise at leastone further transfer which may be arranged such that the reflected lightbeam travels from the measurement chamber plate to the further transferdevice until it may finally impinge on the optical detector. As usedherein, the term “transfer device” refers to an optical element whichmay be configured to transfer the illumination light beam from theillumination source to the measurement chamber plate and/or from themeasurement chamber plate to the optical detector.

The sensor element comprises at least one optical detector designed todetect at least one property of the reflection light beam and togenerate at least one sensor signal dependent on the presence of theanalyte. As used herein, the term “optical detector” refers to a devicewhich is adapted for detecting at least one property of a light beam. Asused herein, the term “sensor signal” generally refers to an arbitrarysignal indicative of the presence of the analyte. As an example, thesensor signal may be or may comprise a digital and/or an analog signal.As an example, the sensor signal may be or may comprise a voltage signaland/or a current signal. Additionally or alternatively, the sensorsignal may be or may comprise digital data. The sensor signal maycomprise a single signal value and/or a series of signal values. Thesensor signal may further comprise an arbitrary signal which is derivedby combining two or more individual signals, such as by averaging two ormore signals and/or by forming a quotient of two or more signals. Theoptical detector may comprise at least one photodetector. The opticaldetector may comprise at least one pyroelectric detector. The opticaldetector may comprise at least one spectrometric setting, for example atleast one Fabry-Pérot interferometer. The optical detector may compriseat least one analog and/or digital amplifier and/or filter in order tofor example amplify at least one property of the reflection light beamand/or reduce noise. As used herein, the term “at least one property ofthe reflection light beam” refers to one or more of intensity,absorbance, attenuation, transmission, reflection, wavelength andfrequency of the reflection light beam. The at least one property of thereflection light beam, for example the intensity, may change due to thepresence of the analyte and/or other substances in the sample of bodyfluid. The optical detector may be adapted to determine a change inintensity, for example due to the presence of the analyte and/or othersubstances in the sample of body fluid. The sensor element may beadapted to perform one or more of at least one reflection measurement,at least one absorption measurement, at least one attenuated totalreflectance measurement. The optical detector may be adapted todetermine at least one absorption information and/or attenuationinformation as a function of wavelength and/or frequency of thereflection light beam. The optical detector may be adapted to determineat least one spectrum, for example at least one absorbance spectrum, ofthe reflection light beam.

The sensor element furthermore comprises at least one control unitdesigned to evaluate the sensor signal. As used herein, the term“control unit” generally refers to an arbitrary element which is adaptedto evaluate the sensor signal. The control unit may be adapted for oneor more of processing, analyzing, and storing of the sensor signal. Thecontrol unit may be a central control unit. The term “data” or“measurement data” refers to both raw sensor signal and processed sensorsignal. As further used within this disclosure, the term “measurementdata” refers to arbitrary data acquired by using the sensor element,indicative of the analyte concentration. The data may specificallycomprise a plurality of measurement values acquired at subsequent pointsin time, such as over a time period of several hours, several days,several weeks or even several months. The data preferably may beacquired in an analogue or digital electronic format. The data furthermay be processed or pre-processed within the control unit, such as byapplying at least one evaluation or pre-evaluation algorithm to thedata. Thus, as an example, at least one algorithm may be applied to thedata, wherein the at least one algorithm transforms primary dataacquired by using the optical detector into secondary data indicatingthe concentration of the analyte in the body fluid, such as by applyinga known or predetermined relationship between the primary data and theanalyte concentration to the primary data, thereby generating secondarydata. Here and in the following, no difference will be made betweenprimary data and secondary data. The control unit may comprise at leastone evaluation device designed to evaluate the sensor signal. Theevaluation device may be designed to generate at least one informationon the analyte by evaluating the sensor signal. As an example, theevaluation device may be or may comprise one or more integratedcircuits, such as one or more application-specific integrated circuits(ASICs), and/or one or more data processing devices, such as one or morecomputers, preferably one or more microcomputers and/ormicrocontrollers. Additional components may be comprised, such as one ormore preprocessing devices and/or data acquisition devices, such as oneor more devices for receiving and/or preprocessing of the sensorsignals, such as one or more AD-converters and/or one or more filters.Further, the evaluation device may comprise one or more data storagedevices. Further, the evaluation device may comprise one or moreinterfaces, such as one or more wireless interfaces and/or one or morewire-bound interfaces. As used herein, the term “at least oneinformation on the analyte” refers to quantitative and/or qualitativeinformation on the analyte. For example, the evaluation device may beadapted to determine at least one spectral information of the reflectionlight beam from the sensor signal. The spectral information may be atleast one absorption spectrum or at least one attenuation spectrum. Forexample, spectra may be acquired by continuously changing the laser'swavelength over time and measuring the sensor signal on the opticaldetector. The difference in absorbance ΔA can be calculated using wateras a reference, I_(ref), byΔA=−log[(I _(meas))/(I _(ref))],with I_(meas) being the sensor signal seen.

The evaluation device may be adapted to determine the analyteconcentration by evaluating the spectral information. The evaluationdevice may be designed to identify characteristic spectral signature ofmolecules in the mid-infrared spectral range. The evaluation device maybe adapted to compare the measured spectral information withpredetermined or theoretical spectral information stored, for example,in an electronic table such as in at least one look-up table. Theevaluation device may be adapted to determine from the spectralinformation the at least one information on the analyte by using uni- ormultivariate data analysis, e.g., principle component regression (PCR)and partial least square regression (PLS). The evaluation device may beadapted to detect and potentially quantify a variety of biomoleculesusing uni- or multivariate data analysis. For example, the evaluationdevice may be adapted to determine the presence and/or concentration ofglucose. The evaluation device may be adapted to identify and/ordetermine a relevant signal or signal component, for example a signalreferring to glucose, and to distinguish the relevant signal fromsignals of interfering molecules. The evaluation device may be adaptedto distinguish the relevant signal from other signal influences such asfrom signal influences due system changes such as temperature.

The control unit, for example the evaluation device, may comprise atleast one or more of amplifier circuits adapted to amplify the sensorsignal and/or to transform the sensor signal into an electrical currentor voltage; at least one analog-/digital converter adapted to digitalizethe sensor signal, for example the amplified sensor signal; at least onedigital filter adapted to optimize a signal-to-noise ratio such as atleast one Lock-In amplifier and/or at least one Boxcar integrator; atleast one analog filter adapted to filter the sensor signal, for examplebefore digitalization; at least one memory unit adapted to store thesensor signal, for example the raw sensor signal and/or the evaluated,for example digitalized and/or amplified, sensor signal. As used herein,a “memory unit” generally may refer to an arbitrary device adapted forcollecting and preferably storing data such as measurement data. Thus,the memory unit generally may comprise at least one data storage devicesuch as at least one volatile and/or at least one non-volatile datastorage element. The components listed above may be designed as separatecomponents within a housing of the sensor element. Alternatively, two ormore of the components as listed above may be integrated into onecomponent. For example, the optical detector may comprise an integratedamplifier circuit and/or one or more signal filters. Additionally oralternatively, one or more of these components may be provided in afurther device situated outside the body of the user. The sensor elementcan be adapted to transfer data, such as the raw sensor signal and/orthe evaluated sensor signal, automatically and/or upon request to thefurther device for evaluation and data storing. The control unit can bedesigned to receive instructions and/or data, for example from thefurther device, contactless, for example via the inductive connection.The sensor element and the further device may be adapted to communicate,i.e., transfer data and instructions, wirelessly such as by an inductiveconnection. Other ways of data transfer, however, are feasible. Thecontrol unit may comprise at least one communication unit for wirelesscommunication. Read-out of the measurement data from the sensor elementmay be performed wireless such that wearing comfort and freedom ofmovement is enhanced.

The evaluation device may be adapted to perform a temperaturecorrection. The sensor signal may be influenced due to temperaturechanges such that drifts in signal may occur. The evaluation device maybe adapted to distinguish signal drift due to temperature change fromsignal drift due to changes in analyte concentration by using spectralinformation. The temperature influence may be corrected usingcalibration data from a prior temperature calibration measurement.Additionally or alternatively, the sensor element may comprise at leastone temperature sensor as for example a platinum resistance thermometer.The temperature sensor may be arranged in close proximity to themeasurement chamber plate. The temperature influence may be correctedusing calibration data from a prior temperature calibration measurementand the measured temperature of the temperature sensor.

The sensor element may comprise at least one housing adapted toencapsulate the further components of the sensor element such as theillumination source, the control unit and the optical detector. Thehousing may allow complete or at least partial implantation of thesensor element within the body of the user. Thus, the housing mayprevent permanent open skin barrier and thus, the housing may preventpenetration of bacteria and other contaminations in the body. Thehousing may be designed to prevent contamination of the sensor element,for example with dirt and moisture. The housing may be biocompatible inorder to reduce and/or minimize specific immune reactions. The housingmay comprise and/or is produced from biocompatible material. Forexample, the biocompatible material may comprise titanium alloy.

The sensor element may comprise at least one rechargeable energy storagedevice. The rechargeable energy storage device may be adapted to supplyvoltage for one or more of the sensor element such as to illuminationsource, the control unit, in particular the amplifier circuit, and theoptical detector, pulser device etc. The control unit may be adapted tocontrol power supply to the components of the sensor element. Forexample, the control unit may be adapted to control power supply to oneor more of the optical detector such as to the amplifier circuit, theillumination source such as the pulser device. The rechargeable energystorage device may be adapted to be charged in a contactless fashion.For example, the rechargeable energy source may be adapted to be chargedwirelessly such as by an inductive connection. Other ways of recharging,however, are feasible. Charging in a contactless fashion may allowlong-term operation without surgical interventions. The rechargeableenergy storage device may comprise at least one lithium-ion battery. Therechargeable energy storage device may be charged by using the furtherdevice situated outside the body of the user such as by using a dockingstation or the like. For example, the further device may be designed tobe worn by the user. The further device may comprise at least onefurther rechargeable energy storage device. The further rechargeableenergy storage device may be adapted to be charged using at least onecable. The further device may be adapted to bring a demand forrecharging the rechargeable energy storage device of the sensor elementto a user's attention, such as in one or more of a visual fashion, anacoustic fashion or a vibrational fashion. Thus, as an example, thefurther device may be adapted to provide at least one of a visualindication, such as a display of an appropriate message, and/or anacoustic indication, such as a warning sound or a voice message, and/ora vibrational indication, such as a vibrational alarm, to a user, inorder to indicate to the user that a recharging of the rechargeableenergy storage device is required. As used herein, a “demand forrecharging” generally may be or may comprise an arbitrary item ofinformation regarding one or both of a status of charge of the at leastone rechargeable energy storage and/or an information indicating that arecharging of the rechargeable energy storage device is necessary inorder to maintain an operation of the sensor element. A “demand”, asused in the context of this disclosure, thus generally may refer to anarbitrary item of information from which a necessity for recharging therechargeable energy storage device may be deduced.

The sensor element may comprise at least one measurement channel and atleast one reference channel. The measurement channel may be designed todetermine the concentration of the analyte. Thus, the measurementchannel may comprise at least the measurement chamber plate adapted toreceive the sample of body fluid. The reference channel may be designedto determine at least one correction information. The reference channelmay comprise at least one reference measurement chamber adapted toreceive at least one reference sample, for example water. The referencemeasurement chamber may not be permeable to fluids. The referencemeasurement chamber may be designed to prevent ingress of the sample ofbody fluid into the reference measurement chamber. The reference channelmay have known or pre-determined beam path of reference illuminationlight beam and/or reference reflection light beam. The beam paths of thereference illumination light beam and/or reference reflection light beammay be identical or similar to beam path of illumination light beamand/or reflection light beam. The reference measurement chamber may haveknown or pre-determined layer thickness. The reference measurementchamber may have identical or similar layer setup and/or thicknesscompared to the measurement chamber plate. The at least one correctioninformation may be determined simultaneously or independent from thedetermination of the analyte. The correction information may comprise atleast one information about a drift correction and/or temperaturecorrection. The evaluation device may be adapted to correct themeasurement data dependent on the correction information.

In a further aspect of this disclosure, a kit for detecting at least oneanalyte in a sample of body fluid is disclosed. The kit comprises atleast one implantable sensor element according to this disclosure and atleast one further device. The further device is adapted to provideenergy to at least one rechargeable energy storage device. For furtherdetails concerning this aspect of this disclosure, reference may be madeto the description of the other aspects of the implantable sensorelement as provided above and/or below.

As used herein, a “kit” is an assembly of a plurality of components,wherein the components each may function and may be handledindependently from each other, wherein the components of the kit mayinteract to perform a common function. Thus, the kit may comprise aplurality of components, wherein each component may be handledindividually, independent from the other components and may perform atleast one function independently, wherein, further, all components orgroups of components comprising at least two of the components may becombined, such as by physically connecting these components, in order toperform a common function implying functionality from the connectedcomponents. The kit comprises the above-mentioned components, i.e., theat least one implantable sensor element and the at least one furtherdevice. As used herein, the term “further device” generally may refer toan arbitrary module of the kit which may be handled independently fromthe sensor element. The further device may be adapted to fulfill atleast one function, such as an analytical function and/or an electricalfunction and/or a medical function and/or computational function. Thecomponents of the kit may be handled independently from each other,i.e., each of the components may have at least one state in which therespective component is not mechanically connected to any othercomponent. Further, each of the components of the kit may have anindividual function, such as a measurement function, a data storagefunction and a data transmission function, which may be exertedindependently from the presence of other components. The further devicemay be situated outside the body of the user, for example the furtherdevice may rest on the skin of the user or may be worn by the user. Thefurther device may be adapted to be placed on a skin or an out-of-bodysurface of the user. Thus, the further device may be an external,extracorporal device. With respect to the definitions and embodiments ofthe further device reference is described to definitions and embodimentsof the further device described with respect to the first aspect of thisdisclosure.

The at least one further device may be adapted to provide electricalenergy to the rechargeable energy storage device in a contactlessfashion, for example via the inductive connection. Other ways ofrecharging, however, are feasible. The sensor element and the kit may beadapted to provide a concept of recharging on-demand for therechargeable energy storage device and thus, allowing long-termoperation.

The at least one further device may comprise at least one portable datamanagement device. The portable data management device may be adapted todirectly or indirectly receive the measurement data and to at leastpartially display data on at least one display. The term “datamanagement device,” as used herein, refers to a device adapted to handlemeasurement data, such as by storing the measurement data and/orsubjecting the measurement data to at least one data evaluationalgorithm. Thus, as an example, the data management device may have atleast one algorithm for displaying the measurement data, such as bydisplaying the measurement data on a display device, thereby displayingone or more measurement curves. Additionally or alternatively, averagingalgorithms may be applied to the measurement data and/or one or morealgorithms adapted to give medical advice to the user. Further, theportable data management device may comprise one or more databases, suchas for storing and/or comparing measurement data.

The at least one further device may comprise at least one data readermodule adapted to receive measurement data transmitted by theimplantable sensor element via wireless communication. The data readermodule may comprise at least one data storage device and may be adaptedto store the measurement data.

In a further aspect of this disclosure, a method for determining aconcentration of at least one analyte in a body fluid of a user isdisclosed. The method comprises the following method steps:

-   -   receiving the sample of body fluid in at least one measurement        chamber plate,    -   generating at least one illumination light beam in at least one        spectral range by using at least one illumination source and        transmitting the illumination light beam to the measurement        chamber plate;    -   at least partially illuminating the measurement chamber plate        with the illumination light beam;    -   generating at least one reflection light beam in response to the        illumination by the illumination light beam;    -   at least partially illuminating the sample of body fluid within        the measurement chamber plate with the reflection light beam;    -   detecting at least one property of the reflection light beam and        generating at least one sensor signal dependent on the presence        of the analyte by using at least one optical detector,    -   evaluating the sensor signal by using at least one control unit.

The method steps may be performed in the given order or in a differentorder. Further, one or more or even all of the method steps may beperformed once or more than once or even repeatedly. The method mayfurther comprise additional method steps which are not listed. In theevaluation step, at least one information on the analyte may begenerated by evaluating the sensor signal.

The method comprises the use of one or both of the sensor elementaccording to this disclosure, such as according to one or more of theembodiments disclosed above or disclosed in further detail below, and/orof the kit according to this disclosure, such as according to one ormore of the embodiments disclosed above or disclosed in further detailbelow. For further optional details, reference may be made to thedisclosure of the sensor element and/or the kit as given above and/or asgiven in further detail below.

The sensor element, the kit and the method according to this disclosureprovide a large number of advantages over known devices for detecting atleast one analyte in body fluid, such as continuous monitoring glucosesensors. The sensor element is a fully implantable sensor element. Thesensor element is based on optical measurements and allows reagent-freeanalyte monitoring. All components as described above can beminiaturized allowing production of very small sensor elements. Thesheet or plate-like geometry ensures mechanical robustness with respectto mechanical influences and thus may ensure signal stability andreliability of measurement data. Further, usage of biocompatiblematerial such as silicon or diamond allows producing an implantablesensor element without additional coatings. Further, using a concept ofrecharging the rechargeable energy storage device of the sensor elementmay allow long-term operation of the sensor element. Thus, the sensorelement may be embodied as a very small and robust module allowingreagent-free and long-term analyte monitoring.

Summarizing the findings of this disclosure, the following embodimentsare preferred. Still, other embodiments are feasible.

Embodiment 1

Implantable sensor element for detecting at least one analyte in asample of body fluid, wherein the sensor element comprises at least onemeasurement chamber plate adapted to receive the sample of bodily fluid,wherein the sensor element comprises at least one illumination sourcedesigned to generate at least one illumination light beam in at leastone spectral range and to transmit the illumination light beam to themeasurement chamber plate such that the illumination light beam at leastpartially illuminates the measurement chamber plate, wherein themeasurement chamber plate is designed to generate at least onereflection light beam in response to the illumination by theillumination light beam such that the reflection light beam at leastpartially illuminates the sample of body fluid within the measurementchamber plate, wherein the sensor element comprises at least one opticaldetector designed to detect at least one property of the reflectionlight beam and to generate at least one sensor signal dependent on thepresence of the analyte, wherein the sensor element furthermorecomprises at least one control unit designed to evaluate the sensorsignal.

Embodiment 2

Implantable sensor element according to the preceding embodiment,wherein the illumination source comprises at least one quantum cascadelaser.

Embodiment 3

Implantable sensor element according to the preceding embodiment,wherein the illumination source comprises at least one quantum cascadelaser chip.

Embodiment 4

Implantable sensor element according to any one of the two precedingembodiments, wherein the quantum cascade laser is selected from thegroup consisting of: at least one fixed-frequency Fabry-Pérot quantumcascade laser; at least one tunable external cavity quantum cascadelaser; at least one distributed feedback quantum cascade laser.

Embodiment 5

Implantable sensor element according to any one of the precedingembodiments, wherein the illumination source is designed to be operatedin pulsed or continuous mode.

Embodiment 6

Implantable sensor element according to the preceding embodiment,wherein the sensor element comprises at least one pulser device adaptedto operate the illumination in the pulse mode, wherein the control unitis adapted to control the pulser device.

Embodiment 7

Implantable sensor element according to any one of the precedingembodiment, wherein the illumination light beam has a wavelength in theinfrared spectral range.

Embodiment 8

Implantable sensor element according to the preceding embodiment,wherein the illumination light beam has a wavelength in the mid-infraredspectral range.

Embodiment 9

Implantable sensor element according to any one of the precedingembodiments, wherein the illumination source is adapted to change thewavelength continuously over time.

Embodiment 10

Implantable sensor element according to any one of the precedingembodiments, wherein the illumination source is adapted to generate aplurality of illumination light beams, wherein each of the illuminationlight beams has a different wavelength.

Embodiment 11

Implantable sensor element according to the preceding embodiment,wherein the control unit is adapted to one or more of assign, adjust orselect the wavelength of the illumination light beams.

Embodiment 12

Implantable sensor element according to any one of the precedingembodiments, wherein the measurement chamber plate comprises at leastone membrane element.

Embodiment 13

Implantable sensor element according to the any one of the precedingembodiments, wherein the measurement chamber plate comprises at leastone chamber wall, wherein the chamber wall is adapted to receive thesample of body fluid.

Embodiment 14

Implantable sensor element according to the preceding embodiment,wherein the measurement chamber plate comprises at least one firstchamber wall adapted to be at least partially transparent to theillumination light beam, wherein the first chamber wall is designed asat least one at least partially transparent first infrared window.

Embodiment 15

Implantable sensor element according to the preceding embodiment,wherein the first chamber wall comprises at least one anti-reflectivecoating adapted to minimize reflections from a surface of the firstchamber wall to the optical detector.

Embodiment 16

Implantable sensor element according to any one of the two precedingembodiments, wherein the measurement chamber plate comprises at leastone second chamber wall adapted to at least partially receive the sampleof body fluid.

Embodiment 17

Implantable sensor element according to the preceding embodiment,wherein the measurement chamber plate comprises at least one capillaryelement arranged between the first chamber wall and the second chamberwall, wherein the capillary element is adapted to receive the sample ofbody fluid.

Embodiment 18

Implantable sensor element according to the preceding embodiment,wherein the measurement chamber plate comprises at least one spacerelement arranged between the first chamber wall and the second chamberwall.

Embodiment 19

Implantable sensor element according to any one of the two precedingembodiments, wherein the second chamber wall is designed as at least oneat least partially reflective second infrared window.

Embodiment 20

Implantable sensor element according to the preceding embodiment,wherein the second infrared window comprises at least one reflectivelayer, wherein the reflective layer is arranged on at least one side ofthe second infrared window facing the illumination light beam in orderto enhance reflection of the illumination light beam.

Embodiment 21

Implantable sensor element according to any one of the two precedingembodiments, wherein the second infrared window is designed to permittransport of the analyte into the capillary element.

Embodiment 22

Implantable sensor element according to the preceding embodiment,wherein the second infrared window comprises at plurality of holes.

Embodiment 23

Implantable sensor element according to any one of the eight precedingembodiments, wherein the second chamber wall comprises the at least onemembrane element.

Embodiment 24

Implantable sensor element according to the preceding embodiment,wherein the second chamber wall is designed as membrane element.

Embodiment 25

Implantable sensor element according to any one of the precedingembodiments, wherein the measurement chamber plate comprises at leastone attenuated total reflection element.

Embodiment 26

Implantable sensor element according to the preceding embodiment,wherein the attenuated total reflection element comprises at least oneATR-crystal, wherein the ATR-crystal is arranged such that theillumination light beam is at least reflected once.

Embodiment 27

Implantable sensor element according to the preceding embodiment,wherein the ATR-crystal comprises a structured surface.

Embodiment 28

Implantable sensor element according to the preceding embodiment,wherein at least one ultra filtration membrane element is arranged onthe ATR-crystal.

Embodiment 29

Implantable sensor element according to any one of the precedingembodiments, wherein the sensor element comprises at least one transferdevice, wherein the transfer device comprises at least one lens.

Embodiment 30

Implantable sensor element according to any one of the precedingembodiments, wherein the optical detector comprises at least onephotodetector.

Embodiment 31

Implantable sensor element according to the preceding embodiment,wherein the optical detector comprises one or more of at least onepyroelectric detector; at least one Fabry-Pérot interferometer.

Embodiment 32

Implantable sensor element according to any one of the precedingembodiments, wherein the control unit is adapted for one or more ofprocessing, analyzing, and storing of the sensor signal.

Embodiment 33

Implantable sensor element according to any one of the precedingembodiments, wherein the control unit comprises at least one evaluationdevice designed to evaluate the sensor signal, wherein the evaluationdevice is designed to generate at least one information on the analyteby evaluating the sensor signal.

Embodiment 34

Implantable sensor element according to the preceding embodiment,wherein the evaluation device is adapted to determine at least onespectral information of the reflection light beam from the sensorsignal.

Embodiment 35

Implantable sensor element according to the preceding embodiment,wherein the evaluation device is adapted to determine from the spectralinformation the at least one information on the analyte by using uni- ormultivariate data analysis, e.g., principle component regression (PCR)and partial least square regression (PLS).

Embodiment 36

Implantable sensor element according to any one of the three precedingembodiments, wherein the evaluation device is adapted to perform atemperature correction.

Embodiment 37

Implantable sensor element according to the preceding embodiments,wherein the control unit comprises at least one or more of amplifiercircuit adapted to amplify the sensor signal and/or to transform thesensor signal into an electrical current or voltage; at least oneanalog-/digital converter adapted to digitalize the sensor signal; atleast one digital filter adapted to optimize a signal-to-noise ratiosuch as at least one Lock-In amplifier and/or at least one Boxcarintegrator; at least one analog filter adapted to filter the sensorsignal; at least one memory unit adapted to store the sensor signal.

Embodiment 38

Implantable sensor element according to the any one of the precedingembodiments, wherein the sensor element comprises at least one housingadapted to encapsulate further components of the sensor element.

Embodiment 39

Implantable sensor element according to any one of the precedingembodiments, wherein the sensor element comprises at least onerechargeable energy storage device.

Embodiment 40

Implantable sensor element according to the preceding claim, wherein therechargeable energy source is adapted to be charged in a contactlessfashion.

Embodiment 41

A kit for detecting at least one analyte in a sample of body fluid, thekit comprising at least one implantable sensor element according to anyone of the preceding embodiments, and at least one further device,wherein the further device is adapted to provide energy to at least onerechargeable energy storage device.

Embodiment 42

The kit according to the preceding embodiment, wherein the at least onefurther device is adapted to provide electrical energy to therechargeable energy storage device in a contactless fashion.

Embodiment 43

The kit according to any one of the preceding embodiments referring to akit, wherein the at least one further device comprises at least one datareader module adapted to receive measurement data transmitted by theimplantable sensor element via wireless communication, wherein the datareader module comprises at least one data storage device and is adaptedto store the measurement data.

Embodiment 44

Method for detecting at least one analyte in a sample of body fluidcomprising the following method steps:

-   -   receiving the sample of body fluid in at least one measurement        chamber plate,    -   generating at least one illumination light beam in at least one        spectral range by using at least one illumination source and        transmitting the illumination light beam to the measurement        chamber plate;    -   at least partially illuminating the measurement chamber plate        with the illumination light beam;    -   generating at least one reflection light beam in response to the        illumination by the illumination light beam;    -   at least partially illuminating the sample of body fluid within        the measurement chamber plate with the reflection light beam;    -   detecting at least one property of the reflection light beam and        generating at least one sensor signal dependent on the presence        of the analyte by using at least one optical detector,    -   evaluating the sensor signal by using at least one control unit.

Embodiment 45

Method according to the preceding embodiment, wherein the methodcomprises a use of one or both of at least one implantable sensorelement according to any one of the preceding embodiments referring toan implantable sensor element or a kit according to any one of thepreceding embodiments referring to a kit.

BRIEF DESCRIPTION OF THE DRAWINGS

The above-mentioned aspects of exemplary embodiments will become moreapparent and will be better understood by reference to the followingdescription of the embodiments taken in conjunction with theaccompanying drawings, wherein:

FIG. 1 shows an exemplary embodiment of an implantable sensor elementand kit according to this disclosure;

FIG. 2 shows a further exemplary embodiment of the implantable sensorelement;

FIG. 3 shows a further exemplary embodiment of the implantable sensorelement; and

FIG. 4 shows a further exemplary embodiment of the fully implantablesensor element.

DESCRIPTION

The embodiments described below are not intended to be exhaustive or tolimit the invention to the precise forms disclosed in the followingdetailed description. Rather, the embodiments are chosen and describedso that others skilled in the art may appreciate and understand theprinciples and practices of this disclosure.

In FIG. 1, an exemplary embodiment of an implantable sensor element 110and a kit 112 for detecting at least one analyte in a body fluid isdisclosed. The sensor element 110 may be designed to remain in the bodytissue for an elongated time period, such as for several days or evenseveral weeks or several months. The sensor element 110 is embodied as afully implantable transcutaneous sensor element. Generally, an arbitrarytype of body fluid may be used. Preferably, the body fluid is a bodyfluid which is present in a body tissue of the user, such as in theinterstitial tissue. Thus, as an example, the body fluid may be selectedfrom the group consisting of blood and interstitial fluid. However,additionally or alternatively, one or more other types of body fluidsmay be used. The body fluid generally may be contained in a body tissue.Thus, generally, the detection of the at least one analyte in the bodyfluid may preferably be determined in vivo.

The sensor element 110 comprises at least one measurement chamber plate114 adapted to receive the sample of bodily fluid. The measurementchamber plate 114 may have a sheet or plate-like geometry. Themeasurement chamber plate 114 may have a flat geometry. The measurementchamber plate 114 may comprise a monolithic or a multi-plate setup. Themeasurement chamber plate 114 may receive the sample of body fluid viadiffusion processes. In FIG. 1, a direction of diffusion of the bodyfluid is denoted with arrow 116. Filling the sample via diffusionprocesses may ensure maintenance-free operation of the implanted sensorelement.

The sensor element 110 comprises at least one illumination source 118designed to generate at least one illumination light beam 120 in atleast one spectral range and to transmit the illumination light beam 120to the measurement chamber plate 114 such that the illumination lightbeam 120 at least partially illuminates the measurement chamber plate114.

The illumination source 118 may comprise at least one light source. Theillumination source 118 comprises at least one quantum cascade laser.For example, the illumination source 118 may comprise at least onequantum cascade laser chip. The quantum cascade laser may be aminiaturized quantum cascade laser. The quantum cascade laser may beselected from the group consisting of: at least one fixed-frequencyFabry-Pérot quantum cascade laser; at least one tunable external cavityquantum cascade laser; at least one distributed feedback quantum cascadelaser. For example, the illumination source 118 may comprise at leastone array of quantum cascade lasers. The illumination source 118 may bedesigned to be operated in pulsed or continuous mode. The sensor element110 may comprise at least one pulser device 122 adapted to operate theillumination in the pulsed mode. The sensor element 110 may comprise atleast one rechargeable energy storage device 124, for example at leastone lithium-ion battery, adapted to supply energy to the quantum cascadelaser. The quantum cascade laser may have a low power consumption suchthat power supply by lithium-ion battery, is possible.

The illumination light beam 120 may have a wavelength in the infraredspectral range, preferably in mid-infrared spectral range. Theillumination source 118 may be adapted to generate broadbandillumination light or illumination light having a narrow bandwidth. Theillumination source 118 may be adapted to change the wavelengthcontinuously over time. The illumination source 118 may be adapted togenerate a plurality of illumination light beams 120, wherein each ofthe illumination light beams has a different wavelength. The sensorelement comprises at least one control unit 126, also referred to hereinas a “controller.” The control unit 126 may be adapted to one or more ofassign, adjust or select the wavelength of the illumination light beams.For example, the illumination source 118 may comprise at least onetunable distributed feedback quantum cascade laser and/or at least onetunable external cavity quantum cascade laser having a narrow bandwidth.The control unit 126 may be adapted to change the wavelengthcontinuously or non-continuously, for example within the mid-infraredspectral range. The control unit 126 may be adapted to adjust and/orselect wavelengths suitable for identification of glucose and/ordistinction of glucose from further substances in the sample of bodyfluid, for example substances present even after filtration such asmaltose. Additionally or alternatively, a broadband spectral range isused. For example, the illumination source 118 may comprise at least oneFabry-Pérot quantum cascade laser. In order to permit absorptionmeasurements with a broadband illumination source, the sensor element110 may comprise several optical detectors and suitable spectralbandpass filters or at least one tunable optical detector having atleast one tunable, spectral bandpass filter.

The illumination light beam 120 may illuminate more than 5% of themeasurement chamber plate 114, preferably more than 10% of themeasurement chamber plate 114, more preferably more than 25% of themeasurement chamber plate 114. However, embodiments are feasible. Theillumination light beam 120 may illuminate the measurement chamber plate114 under an illumination angle between 0° and 85°, preferably between20° and 60°, more preferably between 30° and 50°. For example, theillumination angle may be 45°.

The sensor element 110 may comprise at least one transfer device 128adapted to collimate the illumination light beam 120. The transferdevice 128 may comprise at least one optical lens, such as one or moreconvex lenses, one or more refractive lenses. For example, the transferdevice 128 may be arranged such that the illumination light beam 120travels first through the at least one transfer device 128 andthereafter to the measurement chamber plate 114.

The measurement chamber plate 114 is designed to generate at least onereflection light beam 130 in response to the illumination by theillumination light beam 120 such that the reflection light beam 130 atleast partially illuminates the sample of body fluid within themeasurement chamber plate 114. Preferably, the sample of body fluid isilluminated by the illumination light beam 120 before the sample of bodyfluid is illuminated by the reflection light beam 130. Preferably, thesample of body fluid may be illuminated at least twice within themeasurement chamber plate 114. The sample may be illuminated, firstly,by the illumination light beam 120, for example in a first direction,and, subsequently, by the reflection light beam 130, for example, in asecond direction. The measurement chamber plate 114 may comprise atleast one reflector element and/or may comprise a reflective materialsuch as a reflective coating. The measurement chamber plate 114 may beadapted to at least partially reflect the illumination light beam 120.

The sensor element 110 comprises at least one optical detector 132designed to detect at least one property of the reflection light beam130 and to generate at least one sensor signal dependent on the presenceof the analyte. The sensor signal may be or may comprise a digitaland/or an analog signal. The sensor signal may be or may comprise avoltage signal and/or a current signal. Additionally or alternatively,the sensor signal may be or may comprise digital data. The sensor signalmay comprise a single signal value and/or a series of signal values. Thesensor signal may further comprise an arbitrary signal which is derivedby combining two or more individual signals, such as by averaging two ormore signals and/or by forming a quotient of two or more signals. Theoptical detector 132 may comprise at least one photodetector. Theoptical detector 132 may comprise at least one pyroelectric detector.The optical detector 132 may comprise at least one spectrometricsetting, for example at least one Fabry-Pérot interferometer. Theoptical detector 132 may comprise at least one analog and/or digitalamplifier and/or filter in order to for example amplify at least oneproperty of the reflection light beam 130 and/or reduce noise. Theoptical detector 132 may be adapted to determine one or more ofintensity, absorbance, attenuation, transmission, reflection, wavelengthand frequency of the reflection light beam 130. The at least oneproperty of the reflection light beam 120, for example the intensity,may change due to the presence of the analyte and/or other substances inthe sample of body fluid. The optical detector 132 may be adapted todetermine a change in intensity, for example due to the presence of theanalyte and/or other substances in the sample of body fluid. The sensorelement 110 may be adapted to perform one or more of at least onereflection measurement, at least one absorption measurement, at leastone attenuated total reflectance measurement. The optical detector 132may be adapted to determine at least one absorption information and/orattenuation information as a function of wavelength and/or frequency ofthe reflection light beam 130. The optical detector 132 may be adaptedto determine at least one spectrum, for example at least one absorbancespectrum, of the reflection light beam. The sensor element 110 maycomprise at least one further transfer 128 which may be arranged suchthat the reflected light beam travels from the measurement chamber plate114 to the further transfer device 128 until it may finally impinge onthe optical detector 132.

The sensor element furthermore comprises the at least one control unit126 designed to evaluate the sensor signal. The control unit 126 may beadapted for one or more of processing, analyzing, and storing of thesensor signal. The control unit 126 may be a central control unit. Thecontrol unit 126 may comprise at least one evaluation device 134designed to evaluate the sensor signal. The evaluation device 134 may bedesigned to generate at least one information on the analyte byevaluating the sensor signal. As an example, the evaluation device 134may be or may comprise one or more integrated circuits, such as one ormore application-specific integrated circuits (ASICs), and/or one ormore data processing devices, such as one or more computers, preferablyone or more microcomputers and/or microcontrollers. Additionalcomponents may be comprised, such as one or more preprocessing devicesand/or data acquisition devices, such as one or more devices forreceiving and/or preprocessing of the sensor signals, such as one ormore AD-converters and/or one or more filters. Further, the evaluationdevice 134 may comprise one or more data storage devices. Further, theevaluation device 134 may comprise one or more interfaces, such as oneor more wireless interfaces and/or one or more wire-bound interfaces.The evaluation device 134 may be adapted to determine at least onespectral information of the reflection light beam from the sensorsignal. The spectral information may be at least one absorption spectrumor at least one attenuation spectrum. For example, spectra may beacquired by continuously changing the laser's wavelength over time andmeasuring the sensor signal on the optical detector. The difference inabsorbance ΔA can be calculated using water as a reference, I_(ref), byΔA=−log[(I _(meas))/(I _(ref))],with I_(meas) being the sensor signal seen.

The evaluation device 134 may be adapted to determine the analyteconcentration by evaluating the spectral information. The evaluationdevice 134 may be designed to identify characteristic spectral signatureof molecules in the mid-infrared spectral range. The evaluation device134 may be adapted to compare the measured spectral information withpredetermined or theoretical spectral information stored, for example,in an electronic table such as in at least one look-up table. Theevaluation device 134 may be adapted to determine from the spectralinformation the at least one information on the analyte by using uni- ormultivariate data analysis, e.g., principle component regression (PCR)and partial least square regression (PLS). The evaluation device 134 maybe adapted to detect and potentially quantify a variety of biomoleculesusing uni- or multivariate data analysis. For example, the evaluationdevice 134 may be adapted to determine the presence and/or concentrationof glucose. The evaluation device 134 may be adapted to identify and/ordetermine a relevant signal or signal component, for example a signalreferring to glucose, and to distinguish the relevant signal fromsignals of interfering molecules. The evaluation device 134 may beadapted to distinguish the relevant signal from other signal influencessuch as from signal influences due to system changes such astemperature.

The control unit 126 may comprise at least one or more of amplifiercircuits 136 adapted to amplify the sensor signal and/or to transformthe sensor signal into an electrical current or voltage; at least oneanalog-/digital converter adapted to digitalized the sensor signal, forexample the amplified sensor signal; at least one digital filter adaptedto optimize a signal-to-noise ratio such as at least one Lock-Inamplifier and/or at least one Boxcar integrator; at least one analogfilter adapted to filter the sensor signal, for example beforedigitalization; at least one memory unit 138 adapted to store the sensorsignal, for example the raw sensor signal and/or the evaluated, forexample digitalized and/or amplified, sensor signal. The memory unit 138generally may comprise at least one data storage device such as at leastone volatile and/or at least one non-volatile data storage element. Thecomponents listed above may be designed as separate components within ahousing 140 of the sensor element 110. Alternatively, two or more of thecomponents as listed above may be integrated into one component. Forexample, the optical detector 132 may comprise an integrated amplifiercircuit and/or one or more signal filters. Additionally oralternatively, one or more of these components may be provided in afurther device 142 of the kit 112 situated outside the body of the user.The sensor element 110 can be adapted to transfer data, such as the rawsensor signal and/or the evaluated sensor signal, automatically and/orupon request to the further device 142 for evaluation and data storing.The control unit 126 can be designed to receive instructions and/ordata, for example from the further device 142, contactless, for examplevia the inductive connection. The sensor element and the further devicemay be adapted to communicate, i.e., transfer data and instructions,wirelessly such as by an inductive connection. Other ways of datatransfer, however, are feasible. The control unit 126 may comprise atleast one communication unit 144 for wireless communication. Read-out ofthe measurement data from the sensor element 110 may be performedwireless such that wearing comfort and freedom of movement is enhanced.

The evaluation device 134 may be adapted to perform a temperaturecorrection. The sensor signal may be influenced due to temperaturechanges such that drifts in signal may occur. The evaluation device 134may be adapted to distinguish signal drift due to temperature changefrom signal drift due to changes in analyte concentration by usingspectral information. The temperature influence may be corrected usingcalibration data from a prior temperature calibration measurement.Additionally or alternatively, the sensor element 110 may comprise atleast one temperature sensor as for example a platinum resistancethermometer. The temperature sensor may be arranged in close proximityto the measurement chamber plate 114. The temperature influence may becorrected using calibration data from a prior temperature calibrationmeasurement and the measured temperature of the temperature sensor.

In the embodiments shown in FIGS. 1 and 2, the measurement chamber plate114 may comprise at least one chamber wall 146, wherein the chamber wall146 is adapted to receive the sample of body fluid. The sensor element110 may be adapted to perform at least one measurement based onabsorption spectroscopic techniques using a miniaturized fluid cell. Themeasurement chamber plate 114 may be adapted to receive a sample size ofbody fluid such that a reliable absorption measurement can be performed.For example, a layer thickness of body fluid in the measurement chamberplate 114 may be between 1 μm and 100 μm, preferably between 5 μm and 50μm, more preferably the layer thickness may be between 8 μm and 15 μm.For example, the layer thickness may be 10 μm in order to ensure highsensitivity to detect glucose in aqueous solution. The chamber wall 146may be adapted to have a first side at least partially permeable tolight, for example in the infrared spectral range, and a second side atleast partially permeable to the sample of body fluid. The first side ofthe chamber wall 146 may be at least partially transparent. The chamberwall 146 may be arranged such that the side permeable to the sample ofbody fluid faces an exterior of the sensor element 110.

In the embodiments depicted in FIGS. 1 and 2, the measurement chamberplate 114 may comprise at least one first chamber wall 148 adapted to beat least partially transparent to the illumination light beam 120. Thefirst chamber wall 148 may be designed as at least one at leastpartially transparent first infrared window 150. The first chamber wall148 may be arranged facing an interior of the sensor element 110 such asan interior surrounded by the housing 140. The first chamber wall 148may face the illumination light beam 120. The first infrared window 150may be designed to let at least partially the illumination light beam120 through the infrared window 150 to the sample of body fluid. Forexample, the infrared window 150 may be designed to let at leastpartially the illumination light beam pass 120 through the infraredwindow 150 into the measurement chamber plate 114. The first chamberwall 148 may be designed as transmission window. The first chamber wall148 may be a light-permeable inner plate. The first chamber wall 148 maybe biocompatible. The first chamber wall 148 may comprise and/or may beproduced from at least one biocompatible material. The first chamberwall 148 may consist fully of biocompatible material, for example abiocompatible material comprising at least one synthetic diamond orsilicon. The first chamber wall 148 may comprise at least oneanti-reflective coating adapted to minimize reflections from a surfaceof the first chamber wall 148 to the optical detector 132 and/orreflections of the reflected beam back into the measurement chamberplate 114, for example in order to minimize interference effects on thesignal. The first chamber wall 148 may comprise at least onemicro-structured surface, e.g., roughened surface adapted to minimizereflections from a surface of the first chamber wall to the opticaldetector and/or reflections of the reflected beam back into themeasurement chamber plate 114 for example in order to minimizeinterference effects on the signal.

The measurement chamber plate 114 may comprise at least one secondchamber wall 152 adapted to at least partially receive the sample ofbody fluid. The second chamber wall 152 may be a fluid-permeable outerplate. The measurement chamber plate 114 may comprise at least onecapillary element 154 arranged between the first chamber wall 148 andthe second chamber wall 152. The capillary element 154 may be adapted toreceive the sample of body fluid. The receiving of the sample of bodyfluid may be supported by capillary forces. The first chamber wall 148and the second chamber wall 152 may be arranged at opposing sides of acapillary element 154 and form a measurement cuvette. The capillaryelement 154 may be designed to receive an amount of body fluid requiredfor reliable determination of the analyte. In order to obtain a maximumsensitivity of glucose in aqueous solution, the capillary element may bedesigned to receive a fluid layer thickness between 1 to 100 μm,preferably between 5 and 50 μm, more preferably between 8 and 15 μm. Forexample, the capillary element 154 may be designed to receive a fluidlayer thickness of 10 μm. The capillary element 154 may receive thesample of body fluid via diffusion processes. In order to ensuresuitable sensor response behavior, the capillary element 154 may bedesigned such that diffusion distances are as short as possible,preferably around 100 μm.

The measurement chamber plate 114 may comprise at least one spacerelement 156 arranged between the first chamber wall 148 and the secondchamber wall 152. The spacer element 156 may have an arbitrary shape,for example the spacer element may be at least one ring. The spacerelement may have a thickness between 1 and 100 μm. The spacer element156 may be a cut polyester film. Additionally or alternatively, one ofthe first chamber wall 148 and the second chamber wall 152 may compriseat least one cavity and/or recess, for example produced byphotolithographic methods, adapted to form a capillary element 154.

The second chamber wall 152 may be designed to be rigid againstmechanical influence, for example, during assembling of the sensorelement 110, such that a constant measurement volume can be ensured. Thesecond chamber wall 152 may be designed to be permeable to the analyte,for example, to glucose, such that the analyte can reach the measurementchamber plate. The second chamber wall 152 may be designed to preventlarge-sized molecules and/or cells to penetrate into the measurementchamber plate 114.

In FIG. 1, the second chamber wall 152 may be designed as at least oneat least partially reflective second infrared window 158. The secondinfrared window 158 may comprise at least one reflective layer, forexample a gold layer. The reflective layer may be arranged on at leastone side of the second infrared window 158 facing the illumination lightbeam 120 in order to enhance reflection of the illumination light beam120. The second infrared window 158 may be designed to permit transport,for example by diffusion, of the analyte into the capillary element 154.The second infrared window 158 may be a fluid-permeable outer plate. Thesecond infrared window 158 may comprise a plurality of holes. The secondinfrared window 158 may comprise a plurality of micro fluid channels.For example, the holes may be drilled micro holes having a diameter lessthan 100 μm, preferably less than 20 μm, more preferably less than 10μm. An average distance between two holes may be less than 500 μm,preferably less than 200 μm, more preferably less than 100 μm. Athickness of the second infrared window may be less than 1000 μm,preferably less than 500 μm. Such dimensions may ensure short diffusiontimes of glucose from interstitial fluid into the capillary element. Theholes may have other shapes as for example slits or bendings. The holesmay be produced using laser processing techniques or other methods knownin the art, for example wet etching. The second infrared window 158 maybe or may comprise a silicon plate having a plurality of holes. Such adesign can ensure proper rigidity. The silicon plate may be sputteredwith a gold layer in order to enhance reflectivity. The second chamberwall 152 may have a hydrophilic surface structure on one side and/or onthe other side and/or in the holes of the wall adapted to have betterfluidic properties. This hydrophilic surface may be made by amicrofabricated surface for example by photolithographic or wet etchingmethods.

The measurement chamber plate 114 may comprise at least one membraneelement 160. The membrane element 160 may be adapted to protect themeasurement chamber plate 114 from penetration of particles above acertain size such as large-sized molecules like proteins. In theembodiment of FIG. 1, the measurement chamber plate may comprise a flatmembrane element 160. The flat plate design of the measurement chamberplate 114 may allow simple mounting of the flat membrane element 160. Incase of using the flat membrane element 160, the diffusion distance maybe enhanced only slightly by the thickness of the flat membrane. Themembrane element 160 may be arranged on the side of the second infraredwindow 158. The membrane element 160 may be an ultra filtrationmembrane. The membrane element 160 may be adapted to reduce influencefrom proteins on the absorption measurement. Additionally oralternatively to the membrane element 160, the holes of the secondinfrared window 158 may be designed such that the second infrared windowfunctions as membrane such that no additional membrane element isrequired.

The sensor element 110 may comprise the at least one housing 140 adaptedto encapsulate the further components of the sensor element 110 such asthe illumination source 118, the control unit 126 and the opticaldetector 132. The housing 140 may allow complete or at least partialimplantation of the sensor element 110 within the body of the user.Thus, the housing 140 may prevent permanent open skin barrier and thus,the housing 140 may prevent penetration of bacteria and othercontaminations in the body. The housing 140 may be designed to preventcontamination of the sensor element, for example with dirt and moisture.The housing 140 may be biocompatible in order to reduce and/or minimizespecific immune reactions. The housing 140 may comprise and/or isproduced from biocompatible material. For example, the biocompatiblematerial may comprise titanium alloy.

The sensor element 110 may comprise the at least one rechargeable energystorage device 124, e.g., a battery. The rechargeable energy storagedevice 124 may be adapted to supply voltage for one or more of thesensor element 110 such as to illumination source 118, the control unit126, in particular the amplifier circuit, and the optical detector 132,pulser device 122 etc. The control unit 126 may be adapted to controlpower supply to the components of the sensor element 110. For example,the control unit 126 may be adapted to control power supply to one ormore of the optical detector 132 such as to the amplifier circuit, theillumination source 118 such as the pulser device 122. The rechargeableenergy source 124 may be adapted to be charged in a contactless fashion.For example, the rechargeable energy storage device 124 may be adaptedto be charged wirelessly such as by an inductive connection. Other waysof recharging, however, are feasible. Charging in a contactless fashionmay allow long-term operation without surgical interventions. Therechargeable energy storage device 124 may comprise at least onelithium-ion battery. The rechargeable energy storage device 124 may becharged by using the further device situated outside the body of theuser such as by using a docking station or the like. For example, thefurther device 142 may be designed to be worn by the user. The furtherdevice 142 may comprise at least one further rechargeable energy storagedevice. The further rechargeable energy storage device may be adapted tobe charged using at least one cable. The further device 142 may beadapted to bring a demand for recharging the rechargeable energy storagedevice 124 to a user's attention, such as in one or more of a visualfashion, an acoustic fashion or a vibrational fashion. Thus, as anexample, the further device 142 may be adapted to provide at least oneof a visual indication, such as a display of an appropriate message,and/or an acoustic indication, such as a warning sound or a voicemessage, and/or a vibrational indication, such as a vibrational alarm,to a user, in order to indicate to the user that a recharging of therechargeable energy storage device 124 is required.

As shown in FIG. 1, the kit 112 comprises the at least one implantablesensor element 110 and the at least one further device 142. The furtherdevice 142 may be situated outside the body of the user, for example thefurther device 142 may rest on the skin of the user or may be worn bythe user. The further device 142 may be adapted to be placed on a skinor an out-of-body surface of the user. Thus, the further device 142 maybe an external, extracorporal device. As outlined above, the furtherdevice 142 is adapted to provide energy to at least one rechargeableenergy storage device 124. The at least one further device 142 may beadapted to provide electrical energy to the rechargeable energy storagedevice 124 in a contactless fashion, for example via the inductiveconnection. Other ways of recharging, however, are feasible. The sensorelement 110 and the kit 112 may be adapted to provide a concept ofrecharging on-demand for the rechargeable energy storage device andthus, allowing long-term operation.

In the embodiment shown in FIG. 2, the second chamber wall 152 may bedesigned as membrane element 160. With respect to further elements ofthe sensor element 110 shown in FIG. 2, reference is made to thedescription of FIG. 1 above. The membrane element 160 may havereflective properties. For example, the membrane element 160 maycomprise at least one sintered metal. The membrane element 160 may besputtered with a reflective layer such as a gold, silver or aluminumlayer to enhance reflectivity. For example, the membrane element 160 maybe selected from the group consisting of a track-etched membranecomprising polycarbonate; an Anodisc membrane comprising aluminum oxide;a membrane having a supporting structure such as a polymeric microporousmembrane available from Precision Membranes, LLC; a high-aspect-ratiomembrane comprising silicon and/or carbon available from PrecisionMembranes, LLC; a porous membrane comprising sintered metal. In oneembodiment, the membrane element 160 may be a membrane having asupporting structure such as a polymeric microporous membrane availablefrom Precision Membranes, LLC. The supporting structure may be adaptedto provide rigidity to the measurement chamber plate. The membraneelement 160 having a supporting structure may have a thickness ofseveral 10 μm such that the membrane element 160 can be used as spacerelement 156. In a further embodiment, the membrane element 160 may be ahigh-aspect-ratio membrane comprising silicon and/or carbon availablefrom Precision Membranes, LLC. The high-aspect-ratio membrane may have areflective coating, for example, the membrane element may be sputteredwith a gold layer. However, embodiments are feasible, without areflective coating, e.g., a porous membrane comprising sintered metalhas reflective properties in the infrared spectral range.

In the embodiments shown in FIGS. 3 and 4, the measurement chamber plate114 may comprise at least one attenuated total reflection element 162.With respect to further elements of the sensor element 110 shown inFIGS. 3 and 4, reference is made to the description of FIGS. 1 and 2.The attenuated total reflection element 162 may comprise at least oneATR-crystal, for example an ATR-crystal available from ATR Elements. TheATR-crystal may comprise a structured surface. The ATR-crystal maycomprise at least one microstructure adapted to receive the sample ofbody fluid. The microstructure may enhance amplification of the sensorsignal compared to ATR-crystals without microstructures. Themicrostructure may be adapted as capillary, wherein the receiving of thesample of body fluid may be supported by capillary forces. Themicrostructure may have hydrophilic properties such that themicrostructure is adapted to draw out the body fluid when in contactwith the interstitial fluid. Thereby a transition layer may be formedhaving a fixed thickness in which the reflection measurement can beperformed. The ATR-crystal may be arranged such that the illuminationlight beam 120 is at least reflected once. Preferably, the illuminationlight beam 120 may be reflected several times within the ATR-crystal.The illumination light beam 120 may be collimated by the at least onetransfer device 128, and may impinge on the ATR-crystal. The ATR-crystalmay be designed such that the illumination light beam 120 is reflectedby an area of the ATR-crystal comprising the body fluid. The ATR-crystalmay be biocompatible. The ATR-crystal may comprise or may be producedfrom biocompatible material, for example silicon or diamond. TheATR-crystal may be adapted to reflect the light beam such that itilluminates the optical detector 132, for example after being collimatedby at least one further transfer device 128. In FIG. 3 an embodiment isshown wherein at least one ultra filtration membrane element 160 may bearranged on the ATR-crystal, wherein in FIG. 4 an embodiment without anadditional membrane element 160 is shown.

While exemplary embodiments have been disclosed hereinabove, the presentinvention is not limited to the disclosed embodiments. Instead, thisapplication is intended to cover any variations, uses, or adaptations ofthis disclosure using its general principles. Further, this applicationis intended to cover such departures from the present disclosure as comewithin known or customary practice in the art to which this inventionpertains and which fall within the limits of the appended claims.

LIST OF REFERENCE NUMBERS

-   110 sensor element-   112 kit-   114 measurement chamber plate-   116 direction of diffusion-   118 illumination source-   120 illumination light beam-   122 pulser device-   124 rechargeable energy storage device-   126 control unit-   128 transfer device-   130 reflection light beam-   132 optical detector-   134 evaluation device-   136 amplifier circuit-   138 memory unit-   140 housing-   142 further device-   144 communication unit-   146 chamber wall-   148 first chamber wall-   150 first infrared window-   152 second chamber wall-   154 capillary element-   156 spacer element-   158 second infrared window-   160 membrane element-   162 attenuated total reflection element

What is claimed is:
 1. A fully implantable sensor for detecting at leastone analyte in a sample of body fluid, the sensor comprising: ameasurement chamber plate configured to receive the sample of bodilyfluid; a quantum cascade laser illumination source configured togenerate an illumination light beam in a spectral range and to transmitthe illumination light beam to the measurement chamber plate, wherein:the illumination light beam is configured to at least partiallyilluminate the measurement chamber plate, the measurement chamber plateis configured to generate a reflection light beam in response to theillumination by the illumination light beam, and the reflection lightbeam is configured to at least partially illuminate the sample of bodyfluid within the measurement chamber plate; an optical detectorconfigured to detect at least one property of the reflection light beamand to generate a sensor signal dependent on the presence of theanalyte; and a controller configured to evaluate the sensor signal;wherein the measurement chamber plate comprises first and second chamberwalls forming a capillary adapted to receive the sample of body fluid.2. The fully implantable sensor according to claim 1, wherein thequantum cascade laser is selected from the group consisting of: afixed-frequency Fabry-Pérot quantum cascade laser; a tunable externalcavity quantum cascade laser; a distributed feedback quantum cascadelaser.
 3. The fully implantable sensor according to claim 1, wherein theillumination light beam has a wavelength in the infrared spectral range.4. The fully implantable sensor according to claim 1, whereinmeasurement chamber plate comprises at least one membrane.
 5. The fullyimplantable sensor according to claim 1, wherein the first chamber wallis configured to receive the sample of body fluid.
 6. The fullyimplantable sensor according to claim 5, wherein the first chamber wallis at least partially transparent to the illumination light beam and hasan at least partially transparent first infrared window.
 7. The fullyimplantable sensor according to claim 6, wherein the second chamber wallis adapted to at least partially receive the sample of body fluid. 8.The fully implantable sensor according to claim 7, wherein the secondchamber wall comprises an at least partially reflective second infraredwindow configured for transport of the analyte into the capillary. 9.The fully implantable sensor according to claim 8, wherein the secondchamber wall comprises a membrane.
 10. The fully implantable sensoraccording to claim 1, wherein the measurement chamber plate comprises atleast one attenuated total reflection element having an ATR-crystalarranged to reflect the illumination light beam at least once.
 11. Thefully implantable sensor according to claim 1, wherein the opticaldetector comprises a pyroelectric photodetector.
 12. The fullyimplantable sensor according to claim 1, wherein the controller isconfigured to generate information on the analyte by evaluating thesensor signal.
 13. The fully implantable sensor according to claim 12,wherein the controller is configured to perform a temperaturecorrection.
 14. The fully implantable sensor according to claim 1,wherein the sensor comprises a rechargeable battery configured forcontactless charging.
 15. A kit for detecting at least one analyte in asample of body fluid, the kit comprising: the fully implantable sensoraccording to claim 14; and an energy source configured to provide energyto the battery.
 16. The fully implantable sensor of claim 1, wherein thefirst and second chamber walls define a measurement cuvette.
 17. Amethod for detecting at least one analyte in a sample of body fluid, themethod comprising: receiving the sample of body fluid in a measurementchamber plate; generating an illumination light beam in a spectral rangeand transmitting the illumination light beam to the measurement chamberplate; at least partially illuminating the measurement chamber platewith the illumination light beam; generating at least one reflectionlight beam in response to the illumination by the illumination lightbeam; at least partially illuminating the sample of body fluid withinthe measurement chamber plate with the reflection light beam; detectingat least one property of the reflection light beam and generating atleast one sensor signal dependent on the presence of the analyte byusing at least one optical detector; and evaluating the sensor signalusing a controller; wherein the receiving of the sample of body fluid inthe measurement chamber plate comprises receiving the sample of bodyfluid in a capillary formed by first and second chamber walls.
 18. Themethod according to claim 17, further comprising providing theillumination light beam using a quantum cascade laser.
 19. The method ofclaim 17, comprising providing the measurement chamber plate, a lightsource that generates the illumination light beam, the optical detectorand the controller inside a housing for a fully implantable sensor. 20.The method of claim 19, comprising providing the fully implantablesensor with a rechargeable battery.
 21. A fully implantable sensor fordetecting at least one analyte in a sample of body fluid, the sensorcomprising: a measurement chamber plate configured to receive the sampleof bodily fluid; a quantum cascade laser illumination source configuredto generate an illumination light beam in a spectral range and totransmit the illumination light beam to the measurement chamber plate,wherein: the illumination light beam is configured to at least partiallyilluminate the measurement chamber plate, the measurement chamber plateis configured to generate a reflection light beam in response to theillumination by the illumination light beam, and the reflection lightbeam is configured to at least partially illuminate the sample of bodyfluid within the measurement chamber plate; an optical detectorconfigured to detect at least one property of the reflection light beamand to generate a sensor signal dependent on the presence of theanalyte; and a controller configured to evaluate the sensor signal;wherein the measurement chamber plate comprises an ATR-crystal having amicrostructure adapted to receive the sample of body fluid.
 22. Thefully implantable sensor of claim 21, wherein the microstructure forms acapillary adapted to receive the sample of body fluid.